Correcting genetic misspellings using next-generation Crispr

Sam Burns was my friend. With the wisdom of the sage, he has inspired me and many others on how to make the most of life. He has a rare disease called Progeriahis body aging at a rapid rate, and he died of heart failure at the age of only 17, a courageous life long cut short.

My lab discovered the genetic cause of a toxic disease two decades ago: a single DNA letter gone awry, a T that was supposed to be a C in an important gene called lamin A. The same misspelling was found in all 10 individuals. Approximately 200 individuals worldwide. The world with progeria.

The opportunity to treat this disease by directly fixing misspellings in the relevant body tissue was just science fiction a few years ago. then CRISPR Here it came – the elegant enzymatic device that allows DNA scissors to be delivered to a specific target in the genome. In December 2023, The US Food and Drug Administration (FDA) has approved the first CRISPR-based treatment For sickle cell disease. This approach requires removing bone marrow cells from the body, making a disruptive cut in a specific gene that regulates fetal hemoglobin, treating the patient with chemotherapy to make room in the marrow, and then re-implanting the modified cells. Patients with sickle cell anemia are now being offered lifelong treatment and agonizing attacks of pain for sickle cell anemia, albeit at a very high cost.

For progeria and thousands of other genetic diseases, there are two reasons why this same approach doesn’t work. First, the correction required for most misspellings will usually not be achieved by cutting out the faulty gene. Instead, correction is needed. In the case of progeria, the disease-causing T needs to be edited back into a C. By analogy with a word processor, what is needed is not “find and delete” (first generation Crispr), but “find and replace” (next generation CRISPR). Secondly, spelling errors in the parts of the body most affected by the disease must be corrected. While bone marrow cells, immune cells, and skin cells can be taken out of the body to administer gene therapy, this will not work when the main problem is in the cardiovascular system (as in premature aging) or the brain (as in many cases rare). Genetic diseases). In genetic wizard language, we need… In vivo Options.

The exciting news in 2025 is that these two barriers are starting to collapse. The next generation of CRISPR-based gene editing software, elegantly devised by David Liu of the Broad Institute, allows precise corrective editing of almost any genetic misspelling, without causing the scissors to cut. As for delivery systems, the adeno-associated virus (AAV) family of vectors already offers the potential to deliver In vivo release in the eye, liver and muscle, although there is still much work to be done to improve delivery to other tissues and ensure safety. Non-viral delivery systems such as liposomes nanoparticles are under intense development and may replace viral vectors within a few years.

Working with David Liu, Sam Burns’ mother, and Leslie Gordon of the Progeria Research Foundation, my research group has already shown that a single injection of the drug Progeria is injected into a vein. In vivo A gene editor can significantly extend the lifespan of mice engineered to withstand the human premature aging mutation. Our team is now working to advance this into a human clinical trial. We’re really excited about the possibilities for children with progeria, but this excitement could have an even greater impact. This strategy, if successful, could serve as a model for nearly 7,000 genetic diseases in which the specific misspelling that causes the disease is known, but there is no cure.

There are many hurdles, and cost is a major hurdle as private investment is absent in diseases that affect only a few hundred individuals. However, success in a few rare diseases, supported by government and philanthropic funds, will likely lead to efficiencies and economies that will aid in other applications in the future. This is the best hope for tens of millions of children and adults waiting for treatment. The rare disease community must keep up the pressure. This is what Sam Burns would have wanted.